UNIPROT:P08908 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three pharmacologically distinct high-affinity [3H]serotonin ([3H]5-HT) binding sites were identified in spinal cord synaptosomes. [3H]5-HT competition studies using selective 5-HT1A receptor ligands indicated that approximately 25% of high-affinity synaptosomal [3H]5-HT binding was inhibited by 5-HT1A-selective compounds, an estimate consistent with [3H](+-)-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) saturation experiments in which 5-HT1A receptors were directly labeled. [3H]5-HT competition studies using high-affinity 5-HT1B compounds performed in the presence of 100 nM 8-OH-DPAT (to block 5-HT1A receptors) indicated that approximately 26% of all specific, high-affinity [3H]5-HT binding to spinal cord synaptosomes was to 5-HT1B receptors. [3H]5-HT competition studies performed in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969 (to block 5-HT1A and 5-HT1B receptors, respectively) indicated that the remaining 49% of [3H]5-HT binding did not possess the pharmacologic profile previous reported for 5-HT1C, 5-HT1D, 5-HT1E, 5-HT2, or 5-HT3 receptors. This residual 49% of [3H]5-HT binding to spinal cord synaptosomes observed in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969 (subsequently referred to as "5-HT1S") displayed high affinity and saturability (KD = 4.7 nM) in association/dissociation and saturation experiments. Addition of 300 microM GTP or the nonhydrolyzable form of GTP, 5'-guanylylimidodiphosphate, inhibited [3H]5-HT binding to 5-HT1S receptors in saturation experiments by 35 and 57%, respectively, whereas ATP was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of a novel serotonin receptor subtype (5-HT1S) in rat CNS: interaction with a GTP binding protein. 183 2

Previous investigations (El Mestikawy et al., J Neurochem 51: 1031-1040, 1988) have shown that 5-HT1A binding sites (R[5-HT1A]) solubilized by CHAPS from rat hippocampal membranes can be modulated by guanine nucleotides, as expected from their solubilization together with associated G regulatory proteins (G). Studies of the hydrodynamic properties of solubilized R[5-HT1A] have been presently carried out in order to assess in a more direct way the presence of R[5-HT1A]-G complexes in the soluble extract. Under control conditions, the sedimentation of a CHAPS extract from hippocampal membranes through a 5-30% sucrose gradient (200,000 g, 17 hr, 4 degrees) gave two maxima of [3H]8-OH-DPAT binding activity corresponding to sedimentation coefficients of 8.0 S and 10.0 S, respectively. Running the gradient in the presence of 1 microM GTP revealed a significant reduction of the 10.0 S peak, as expected from the loss of material (probably a G protein) normally associated with R[5-HT1A]. Conversely, attempts to prevent the dissociation of R[5-HT1A]-G by treatment of CHAPS soluble hippocampal extracts with the cross-linking reagent disuccinimidyl suberate (0.1 mM) resulted in a significant increase (+70%) in [3H]8-OH-DPAT binding activity associated with the appearance of a new sedimenting material with a higher coefficient (16.5 S). Furthermore, [3H]8-OH-DPAT binding became almost completely insensitive to guanine nucleotides as expected from the irreversible coupling by disuccinimidyl suberate of R[5-HT1A] with G protein(s). WGA-agarose chromatography of CHAPS soluble hippocampal extract supplemented with GTP allowed the physical separation of R[5-HT1A] from the bulk of G proteins, and a concomitant decrease of [3H]8-OH-DPAT high affinity binding capacity. Partial recovery of the latter could be achieved by reconstituting R[5-HT1A]-G complexes upon the addition of a mixture of pure bovine Gi + Go to G-deprived soluble extracts. Finally in vivo treatment with Pertussis toxin (5 micrograms intracerebroventricularly, 48 hr before killing) resulted in a significant reduction of the specific binding of [3H]8-OH-DPAT (-36%) to hippocampal membranes and corresponding CHAPS soluble extracts, and a marked decrease in the inhibitory effect of GppNHp. Accordingly the G protein associated with R[5-HT1A] belongs probably to the Gi or Go families.
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PMID:Physical evidence of the coupling of solubilized 5-HT1A binding sites with G regulatory proteins. 213 95

Eltoprazine (DU 28853) inhibits offensive aggressive behaviour in several animal species. We characterized the binding of radiolabelled eltoprazine in rat brain by autoradiography. [3H]Eltoprazine displayed saturable and high-affinity binding to several brain areas, including the basal ganglia, hippocampal formation and cerebral cortex (Kd values ranging from 4.2 to 9.5 nM). The maximal binding capacities (Bmax) for [3H]eltoprazine were similar to those for [3H]5-HT and were highest in the substantia nigra and subiculum. Competition with eltoprazine for [3H]ligand binding to the various 5-HT1 receptor subtypes revealed preferential binding to 5-HT1A (IC50 values ranging from 42 to 50 nM) and 5-HT1B (IC50 values ranging from 25 to 38 nM) recognition sites. The drug had moderate affinity for 5-HT1C sites (IC50 = 282 nM). Addition of GTP or its stable analogue Gpp(NH)p to the radioligand assay caused a marked reduction (50-90%) in both [3H]eltoprazine and [3H]5-HT binding. These effects were substantially less in the choroid plexus. The binding of the antagonist (-)[125I]Iodocyanopindolol ([125I]ICYP) to 5-HT1B recognition sites, as quantified in the subiculum and substantia nigra, was either unaltered or slightly enhanced by the addition of 10(-3) M GTP. Furthermore, GTP did not affect the competition for [125I]ICYP binding by the 5-HT1-antagonist methiothepin, whereas it did significantly reduce the displacement by eltoprazine, resulting in an almost twofold increase in IC50 values. The data indicate that the anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor sites and that this interaction is modulated by guanine nucleotides.
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PMID:The anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor subtypes in rat brain: sensitivity to guanine nucleotides. 227 61

NAN-190 has been reported to be a 5-HT1A antagonist in drug discrimination studies. In order to determine if the effect of NAN-190 was directly due to competitive inhibition at 5-HT1A receptors, 5-HT1A-mediated inhibition of adenylyl cyclase in hippocampal membranes was investigated. NAN-190 (10(-10)-10(-5) M), by itself, was found to have no effect on forskolin-stimulated adenylyl cyclase. NAN-190, however, did shift the 5-carboxamidotryptamine (a 5-HT1A agonist) log-concentration inhibition curve to the right in a concentration-dependent manner, typical of competitive antagonism. Schild analysis revealed a KB of 1.9 nM for NAN-190. Thus, NAN-190 appeared to be a potent competitive 5-HT1A antagonist using the in vitro adenylyl cyclase system. [3H]NAN-190 was synthesized and its 5-HT1A receptor binding properties were characterized and compared with the 5-HT1A agonist radioligand, [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT). The 5-HT1A agonists, serotonin (5-HT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) competed with equal affinities regardless of the radioligand used to label the 5-HT1A receptors. [3H]NAN-190 and [3H]8-OH-DPAT labeled the same number of sites in rat hippocampus, striatum and frontal cortex. Guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) and 5-guanylyl-imidodiphosphate (GppNHp), non-hydrolyzable analogs of GTP, inhibited specific [3H]NAN-190 binding. Adenosine-5'-O-(3-thio)triphosphate (ATP gamma S) and 5-adenylyl-imidodiphosphate (AppNHp) were ineffective. This guanylyl nucleotide-specific effect is generally associated with agonist radioligand binding to a GTP-binding protein coupled receptor. However, [3H]8-OH-DPAT was far more sensitive than [3H]NAN-190 to the Bmax reducing effects of GTP and GTp gamma S. We propose that the test for a reduction in Bmax by non-hydrolyzable guanylyl nucleotides may be more sensitive than other tests for quantifying agonist activity and may demonstrate that NAN-190 has low intrinsic activity. In summary, NAN-190 displayed antagonist-like properties in functional models of 5-HT1A receptor activity and possibly partial agonist-like properties in radioligand binding experiments.
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PMID:NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors. 228 13

Serotonin (5-hydroxytryptamine; 5-HT) and its analogs activate adenylate cyclase in membrane particles from neuroblastoma NCB.20 cells. Low concentrations of GTP (EC50 = 60 nM) were required for activation by serotonin. Guanosine 5'-O-(2-thiodiphosphate) inhibited serotonin-activated cyclase in these cells. The nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (EC50 = 3 nM) and guanylyl-imidodiphosphate (EC50 = 100 nM) substituted for GTP in potentiating serotonin activation. Pretreatment of the cells with cholera toxin potentiated enzyme activation by serotonin, whereas pertussis toxin was found to have little effect, indicating the involvement of the alpha subunit of a stimulatory GTP-binding protein in enzyme activation. Homologous desensitization of the serotonin-stimulated adenylate cyclase was demonstrated in membranes prepared from intact cells pretreated with serotonin. Cell membrane particles that were desensitized to serotonin were still responsive to beta-adrenergic agonists and to prostaglandin E1. Evidence is presented indicating that serotonin stimulation of adenylate cyclase is mediated by receptors that are distinct from other positively coupled receptors (beta-adrenergic, histamine, and prostacyclin). Equilibrium binding analysis with [3H]serotonin, [3H]lysergic acid diethylamide, and [3H]dihydroergotamine suggested that the site density was below the level of detection of binding of these radioligands. The pharmacological characteristics of the serotonin-activated cyclases were analyzed in order to compare these serotonin receptors with the family of different receptor subtypes. Correlation analysis between the potencies of different agonists and antagonists at the cyclase in these cells and their reported relative potencies for different serotonin receptor subtypes showed no correlation with the 5-HT1A, 5HT1B, 5HT1D, 5-HT2, and 5-HT3 receptors. On the other hand, the analysis showed that the NCB.20 serotonin receptors are similar but not identical to the rat and pig brain 5-HT1C receptors and to the serotonin receptors coupled to adenylate cyclase in the trematodes Schistosoma mansoni and Fasciola hepatica. The results point to a novel serotonin receptor which has a low density in these cells.
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PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46

High-affinity, specific 3H-5-hydroxytryptamine (5-HT) binding was analyzed in membrane homogenates of human frontal cortex, caudate, and globus pallidus. 5-HT1A and 5-HT1C binding sites were pharmacologically blocked using 100 nM 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) and 100 nM mesulergine, respectively. The majority of 5-HT1 sites remained in each of the three brain regions under these conditions. The pattern of nucleotide interactions with these binding sites (GppNHp = GTP = GDP greater than GMP = adenine nucleotides) suggests a possible linkage to a G protein. RU 24969 competition studies confirmed the absence of 5-HT1B binding sites in human cortex, caudate, and globus pallidus. Drug interactions with putative 5-HT1D binding sites in bovine caudate membranes correlated significantly with their affinities for human membrane recognition sites labeled by 3H-5-HT in the presence of 100 nM 8-OH-DPAT + 100 nM mesulergine. We conclude that the majority of 3H-5-HT labeled recognition sites in human cortex, caudate, and globus pallidus represent 5-HT1D binding sites.
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PMID:Identification of 5-hydroxytryptamine1D binding sites in human brain membranes. 252 59

The potential interaction of CM 57493 [4-(3-trifluoromethyl-phenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyri din e] with central 5-hydroxytryptamine (5-HT) receptors was assessed using biochemical and electrophysiological tests in the rat and in the cat. In vitro binding assays with rat brain membranes revealed that CM 57493 bound to 5-HT1A sites in a concentration range (pIC50 = 7.1) at least two orders of magnitude lower than that required for its interaction with 5-HT1B/5-HT1D, 5-HT2, 5-HT3 and 5-HTPre sites. The affinity of CM 57493 for 5-HT1A sites labeled by [3H]-8-OH-DPAT in hippocampal membranes was enhanced by Mn++ and reduced by GTP, as expected for an agonist. Like 8-OH-DPAT, CM 57493 inhibited forskolin-activated adenylate cyclase activity in hippocampal homogenates. The inhibitory effects of these two compounds were not additive and were prevented by 5-HT1A antagonists such as spiperone and dl-propranolol. In vivo treatment with CM 57493 decreased the levels of 5-hydroxyindole acetic acid in various brain areas, as observed with other 5-HT1A agonists such as 8-OH-DPAT and ipsapirone. Electrophysiological recording within the dorsal raphe nucleus in chloral hydrate anesthetized rats showed that CM 57493 administration induced a dose-dependent reduction of the spontaneous firing of serotoninergic neurons. In vitro, CM 57493 (5-20 microM) also reduced neuronal firing in the nucleus raphe dorsalis within brainstem slice, and this effect could be prevented by dl-propranolol. Finally, in cats pretreated with reserpine, CM 57493 induced a decrease in ponto-geniculo-occipital activity, which could be antagonized by methiothepin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical and electrophysiological evidence for an agonist action of CM 57493 at pre- and postsynaptic 5-hydroxytryptamine1A receptors in brain. 252 86

The effects of ethanol on serotonin (5-hydroxytryptamine, 5-HT) receptor binding in rat and mouse brain were determined under in vitro conditions and in mouse brain following seven days of ethanol ingestion. 5-HT1A receptor characteristics were measured utilizing the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([ 3H]DPAT), and 5HT2 receptor-binding studies utilized the antagonist [3H]ketanserin. At the highest concentration of ethanol tested in vitro (680 mM), there was only 25% inhibition of [3H]DPAT binding in rat and mouse brain and 14% inhibition of [3H]ketanserin binding in rat brain. Effects of an anesthetic concentration of ethanol (100 mM) on agonist binding in the presence and absence of the guanine nucleotide GTP were also evaluated in vitro in mouse brain. In no case did ethanol (100 mM) significantly affect 5-HT1A or 5-HT2 receptor-binding characteristics. When 5-HT receptor characteristics were measured after mice consumed ethanol for seven days, there was no change in either 5-HT1A or 5-HT2 receptor-binding properties in any of the brain areas examined.
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PMID:Ethanol does not affect serotonin receptor binding in rodent brain. 252 20

We have previously reported the presence of a 5-HT1 (serotonin)-like receptor coupled in an inhibitory manner to adenylate cyclase in the opossum kidney cell line, which is derived from the kidney of a North American opossum. Pharmacological data from binding and cyclic AMP production studies indicate that this receptor does not have characteristics of a 5-HT1A, 5-HT1C or 5-HT1D receptor, but is similar to 5-HT1B receptors found in rodent tissues. Many serotonergic drugs, including 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyrindinyl)1H-indol, 5-HT and methysergide, but not (+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide or buspirone, were full agonists at this receptor as defined by the inhibition of bovine parathyroid hormone peptide fragment 1-34-stimulated cyclic AMP production in an intact cell assay. Several classical beta adrenergic antagonists including propranolol and cyanopindolol were also full agonists at this receptor. Radioligand binding studies using [125I](-)-iodocyanopindolol gave a Bmax of 88 fmol/mg of protein and a KD of 47 pM for saturation experiments carried out in the presence of GTP. In the absence of GTP, the binding data were significantly better fit by a two-site model with KD values of 10 and 345 pM. Inhibition binding experiments were consistent with the results of the cyclic AMP experiments. The identification of 5-HT1B receptors in a tissue derived from the opossum kidney suggests that these receptors may be distributed more widely than previously thought, inasmuch as other studies have found them only in neuronal tissues of rodents.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of serotonin-1B receptors negatively coupled to adenylate cyclase in OK cells, a renal epithelial cell line from the opossum. 254 34

[3H]5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). [3H]5-HT labeled both 5-HT1A and 5-HT1C recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific [3H]5-HT binding. Saturation experiments of [3H]5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT1A and 5-HT1C sites revealed that non-5-HT1A/non-5-HT1C sites represented about 60% of the total 5-HT1 sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT1A/non-5-HT1C sites (designated 5-HT1R) also differed from that of 5-HT1B and 5-HT2 sites, but was similar to that of the 5-HT1D site. However, significant differences existed between the 5-HT1D and 5-HT1R sites for their Ki values for spiperone, spirilene (an analog of spiperone), metergoline, and methiothepin. The study of modulatory agents (calcium and GTP) also showed differences between the 5-HT1R and 5-HT1D sites. For example, the effects of GTP on agonist binding to the 5-HT1R sites were less than on the 5-HT1D sites in bovine caudate. In addition, calcium enhanced the effects of GTP on the 5-HT1R sites, whereas calcium inhibited the GTP effect on the 5-HT1D sites. The present findings demonstrate the presence of a high-affinity [3H]5-HT binding site in rabbit CN, designated 5-HT1R, that is different from previously defined 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 sites.
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PMID:Characterization of a [3H]-5-hydroxytryptamine binding site in rabbit caudate nucleus that differs from the 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D subtypes. 281

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